Structure-Based Identification of Novel Histone Deacetylase 4 (HDAC4) Inhibitors.

Histone deacetylases (HDACs) are important cancer drug targets. Existing FDA-approved drugs target the catalytic pocket of HDACs, which is conserved across subfamilies (classes) of HDAC. However, engineering specificity is an important goal. Herein, we use molecular modeling approaches to identify and target potential novel pockets specific to Class IIA HDAC-HDAC4 at the interface between HDAC4 and the transcriptional corepressor component protein NCoR. These pockets were screened using an ensemble docking approach combined with consensus scoring to identify compounds with a different binding mechanism than the currently known HDAC modulators. Binding was compared in experimental assays between HDAC4 and HDAC3, which belong to a different family of HDACs. HDAC4 was significantly inhibited by compound 88402 but not HDAC3. Two other compounds (67436 and 134199) had IC50 values in the low micromolar range for both HDACs, which is comparable to the known inhibitor of HDAC4, SAHA (Vorinostat). However, both of these compounds were significantly weaker inhibitors of HDAC3 than SAHA and thus more selective, albeit to a limited extent. Five compounds exhibited activity on human breast carcinoma and/or urothelial carcinoma cell lines. The present result suggests potential mechanistic and chemical approaches for developing selective HDAC4 modulators.

Pterostilbene Reverses Epigenetic Silencing of Nrf2 and Enhances Antioxidant Response in Endothelial Cells in Hyperglycemic Microenvironment.

The epigenetic regulation of nuclear factor erythroid 2-related factor 2 (Nrf2), a pivotal redox transcription factor, plays a crucial role in maintaining cellular homeostasis. Recent research has underscored the significance of epigenetic modifications of Nrf2 in the pathogenesis of diabetic foot ulcers (DFUs). This study investigates the epigenetic reversal of Nrf2 by pterostilbene (PTS) in human endothelial cells in a hyperglycemic microenvironment (HGM). The activation potential of PTS on Nrf2 was evaluated through ARE-Luciferase reporter assays and nuclear translocation studies. Following 72 h of exposure to an HGM, mRNA expression and protein levels of Nrf2 and its downstream targets NAD(P)H quinone oxidoreductase 1 (NQO1), heme-oxygenase 1(HO-1), superoxide dismutase (SOD), and catalase (CAT) exhibited a decrease, which was mitigated in PTS-pretreated endothelial cells. Epigenetic markers, including histone deacetylases (HDACs class I-IV) and DNA methyltransferases (DNMTs 1/3A and 3B), were found to be downregulated under diabetic conditions. Specifically, Nrf2-associated HDACs, including HDAC1, HDAC2, HDAC3, and HDAC4, were upregulated in HGM-induced endothelial cells. This upregulation was reversed in PTS-pretreated cells, except for HDAC2, which exhibited elevated expression in endothelial cells treated with PTS in a hyperglycemic microenvironment. Additionally, PTS was observed to reverse the activity of the methyltransferase enzyme DNMT. Furthermore, CpG islands in the Nrf2 promoter were hypermethylated in cells exposed to an HGM, a phenomenon potentially counteracted by PTS pretreatment, as shown by methyl-sensitive restriction enzyme PCR (MSRE-qPCR) analysis. Collectively, our findings highlight the ability of PTS to epigenetically regulate Nrf2 expression under hyperglycemic conditions, suggesting its therapeutic potential in managing diabetic complications.

Crucial Structural Understanding for Selective HDAC8 Inhibition: Common Pharmacophores, Molecular Docking, Molecular Dynamics, and Zinc Binder Analysis of selective HDAC8 inhibitors.

BACKGROUND: Overexpression of HDAC8 was observed in various cancers and inhibition of HDAC8 has emerged as a promising therapeutic approach in recent decades. OBJECTIVE: This review aims to facilitate the discovery of novel selective HDAC8 inhibitors by analyzing the structural scaffolds of 66 known selective HDAC8 inhibitors, along with their IC50 values against HDAC8 and other HDACs. METHODS: The inhibitors were clustered based on structural symmetry, and common pharmacophores for each cluster were identified using Phase. Molecular docking with all HDACs was performed to determine binding affinity and crucial interacting residues for HDAC8 inhibition. Representative inhibitors from each cluster were subjected to molecular dynamics simulation to analyze RMSD, RMSF, active site amino acid residues, and crucial interacting residues responsible for HDAC8 inhibition. The study reviewed the active site amino acid information, active site cavities of all HDACs, and the basic structure of Zn2+ binding groups. RESULTS: Common pharmacophores identified included AADHR_1, AADDR_1, ADDR_1, ADHHR_1, and AADRR_1. Molecular docking analysis revealed crucial interacting residues: HIS- 142, GLY-151, HIS-143, PHE-152, PHE-20 in the main pocket, and ARG-37, TYR-100, TYR-111, TYR-306 in the secondary pocket. The RMSD of protein and RMSF of active site amino acid residues for stable protein-ligand complexes were less than 2.4 Å and 1.0 Å, respectively, as identified from MD trajectories. The range of Molecular Mechanics Generalized Born Surface Area (MMGBSA) ΔG predicted from MD trajectories was between -15.8379 Å and -61.5017 Å kcal/mol. CONCLUSION: These findings may expedite the rapid discovery of selective HDAC8 inhibitors subject to experimental evaluation.

The histone deacetylase inhibitor MS-275 enhances the matrix mineralization of dental pulp stem cells by inducing fibronectin expression.

Background/purpose: The acetylation of histone H3 proteins keeps local chromatin regions open and accessible, thereby facilitating transcriptional events. We recently reported integrative epigenomic and transcriptome analyses of differentiating dental pulp stem cells (DPSCs). A significant increase in the number of super-enhancers, which are local genomic locations marked by condensed open chromatin peaks that facilitate transcriptional events, in differentiating DPSCs were observed. However, it is still unclear whether histone deacetylase (HDACs) inhibitors (HDACis) have beneficial effects on the odontogenic differentiation of DPSCs and on the matrix mineralization-inducing ability of DPSCs. Materials and methods: DPSCs were cultured in an odontogenic induction medium for a prolonged period in the presence of HDACis, MS-275 and Trichostatin A (TSA). ATAC-seq and RNA-seq samples were collected from differentiating DPSCs to explore the epigenomic and transcriptomic alterations induced by HDACis and identify key target proteins that mediate HDACis-induced phenotypic changes. Results: MS-275 and TSA did not change whole-genome open chromatin accessibility or increase odontogenic differentiation, as assessed by alkaline phosphate activity. However, the matrix mineralization-inducing ability assessed by calcified nodule formation was significantly increased by MS-275 but not by TSA. FN1, which encodes fibronectin, was identified as upregulated by MS-275. The knockdown of fibronectin evidently suppressed MS-275-induced calcified nodule formation. Conclusion: MS-275 induced calcified nodule formation by the mechanistic upregulation of FN1, independent of epigenomic alterations. Hence, the application of MS-275 as direct capping materials has therapeutic potential for promoting reparative dentin formation by constructing a fibronectin-organizing physiological extracellular matrix environment that is adequate for matrix mineralization.

Preliminary study on the mechanism of SAHA in the treatment of refractory epilepsy induced by GABRG2(F343L) mutation.

Mutations in the γ-amino butyric acid type A (GABAA) receptor γ2 subunit gene, GABRG2, have been associated with refractory epilepsy. Increasing evidence indicates that suberoylanilide hydroxamic acid (SAHA), a broad-spectrum histone acetyltransferases (HDACs) inhibitor, can inhibit seizure onset. However, the mechanisms involved remains unknown. The present study aimed to explore the anti-epileptic effect and underlying mechanisms of SAHA in the treatment of refractory epilepsy induced by GABRG2 mutation. In the zebrafish line expressing human mutant GABRG2(F343L), Tg(hGABRG2F343L), SAHA was found to reduce seizure onset, swimming activity, and neuronal activity. In both Tg(hGABRG2F343L) zebrafish and HEK293T cells transfected with GABAA receptor subunits, SAHA could improve the pan-acetylation level and reduce the expression of HDAC1/10. The decreased expressions of GABAA receptor subunits could be rescued by SAHA treatment both in vivo and in vitro, which might be the result of increased gene transcription and protein trafficking. The up-regulated acetylation of histone H3 and H4 as well as Bip expression might be involved in the process. Taken together, our data proved that both histone and non-histone acetylation might contribute to the anti-epileptic effect of SAHA in refractory epilepsy caused by GABRG2(F343L) mutation, demonstrating SAHA as a promising therapeutic agent for refractory epilepsy.

HDAC3 inhibitors: a patent review of their broad-spectrum applications as therapeutic agents.

INTRODUCTION: Histone deacetylases (HDACs) are a class of zinc-dependent enzymes. They maintain acetylation homeostasis, with numerous biological functions and are associated with many diseases. HDAC3 strictly requires multi-subunit complex formation for activity. It is associated with the progression of numerous non-communicable diseases. Its widespread involvement in diseases makes it an epigenetic drug target. Preexisting HDAC3 inhibitors have many uses, highlighting the need for continued research in the discovery of HDAC3-selective inhibitors. AREA COVERED: This review provides an overview of 24 patents published from 2010 to 2023, focusing on compounds that inhibit the HDAC3 isoenzyme. EXPERT OPINION: HDAC3-selective inhibitors - pivotal for pharmacological applications, as single or combination therapies - are gaining traction as a strategy to move away from complications laden pan-HDAC inhibitors. Moreover, there is an unmet need for HDAC3 inhibitors with alternative zinc-binding groups (ZBGs) because some preexisting ZBGs have limitations related to toxicity and side effects. Difficulties in achieving HDAC3 selectivity may be due to isoform selectivity. However, advancements in computer-aided drug design and experimental data of HDAC3 3D co-crystallized models could lead to the discovery of novel HDAC3-selective inhibitors, which bear alternative ZBGs with balanced selectivity for HDAC3 and potency.

Reactivity-Tunable Fluorescent Platform for Selective and Biocompatible Modification of Cysteine or Lysine.

Chemoselective modification of specific residues within a given protein poses a significant challenge, as the microenvironment of amino acid residues in proteins is variable. Developing a universal molecular platform with tunable chemical warheads can provide powerful tools for precisely labeling specific amino acids in proteins. Cysteine and lysine are hot targets for chemoselective modification, but current cysteine/lysine-selective warheads face challenges due to cross-reactivity and unstable reaction products. In this study, a versatile fluorescent platform is developed for highly selective modification of cysteine/lysine under biocompatible conditions. Chloro- or phenoxy-substituted NBSe derivatives effectively labeled cysteine residues in the cellular proteome with high specificity. This finding also led to the development of phenoxy-NBSe phototheragnostic for the diagnosis and activatable photodynamic therapy of GSH-overexpressed cancer cells. Conversely, alkoxy-NBSe derivatives are engineered to selectively react with lysine residues in the cellular environment, exhibiting excellent anti-interfering ability against thiols. Leveraging a proximity-driven approach, alkoxy-NBSe probes are successfully designed to demonstrate their utility in bioimaging of lysine deacetylase activity. This study also achieves integrating a small photosensitizer into lysine residues of proteins in a regioselective manner, achieving photoablation of cancer cells activated by overexpressed proteins.

Exploring histone deacetylases in type 2 diabetes mellitus: pathophysiological insights and therapeutic avenues.

Diabetes mellitus is a chronic disease that impairs metabolism, and its prevalence has reached an epidemic proportion globally. Most people affected are with type 2 diabetes mellitus (T2DM), which is caused by a decline in the numbers or functioning of pancreatic endocrine islet cells, specifically the ß-cells that release insulin in sufficient quantity to overcome any insulin resistance of the metabolic tissues. Genetic and epigenetic factors have been implicated as the main contributors to the T2DM. Epigenetic modifiers, histone deacetylases (HDACs), are enzymes that remove acetyl groups from histones and play an important role in a variety of molecular processes, including pancreatic cell destiny, insulin release, insulin production, insulin signalling, and glucose metabolism. HDACs also govern other regulatory processes related to diabetes, such as oxidative stress, inflammation, apoptosis, and fibrosis, revealed by network and functional analysis. This review explains the current understanding of the function of HDACs in diabetic pathophysiology, the inhibitory role of various HDAC inhibitors (HDACi), and their functional importance as biomarkers and possible therapeutic targets for T2DM. While their role in T2DM is still emerging, a better understanding of the role of HDACi may be relevant in improving insulin sensitivity, protecting ß-cells and reducing T2DM-associated complications, among others.

The Histone Deacetylase Family: Structural Features and Application of Combined Computational Methods.

Histone deacetylases (HDACs) are crucial in gene transcription, removing acetyl groups from histones. They also influence the deacetylation of non-histone proteins, contributing to the regulation of various biological processes. Thus, HDACs play pivotal roles in various diseases, including cancer, neurodegenerative disorders, and inflammatory conditions, highlighting their potential as therapeutic targets. This paper reviews the structure and function of the four classes of human HDACs. While four HDAC inhibitors are currently available for treating hematological malignancies, numerous others are undergoing clinical trials. However, their non-selective toxicity necessitates ongoing research into safer and more efficient class-selective or isoform-selective inhibitors. Computational methods have aided the discovery of HDAC inhibitors with the desired potency and/or selectivity. These methods include ligand-based approaches, such as scaffold hopping, pharmacophore modeling, three-dimensional quantitative structure-activity relationships, and structure-based virtual screening (molecular docking). Moreover, recent developments in the field of molecular dynamics simulations, combined with Poisson-Boltzmann/molecular mechanics generalized Born surface area techniques, have improved the prediction of ligand binding affinity. In this review, we delve into the ways in which these methods have contributed to designing and identifying HDAC inhibitors.

Decrypting lysine deacetylase inhibitor action and protein modifications by dose-resolved proteomics.

Lysine deacetylase inhibitors (KDACis) are approved drugs for cutaneous T cell lymphoma (CTCL), peripheral T cell lymphoma (PTCL), and multiple myeloma, but many aspects of their cellular mechanism of action (MoA) and substantial toxicity are not well understood. To shed more light on how KDACis elicit cellular responses, we systematically measured dose-dependent changes in acetylation, phosphorylation, and protein expression in response to 21 clinical and pre-clinical KDACis. The resulting 862,000 dose-response curves revealed, for instance, limited cellular specificity of histone deacetylase (HDAC) 1, 2, 3, and 6 inhibitors; strong cross-talk between acetylation and phosphorylation pathways; localization of most drug-responsive acetylation sites to intrinsically disordered regions (IDRs); an underappreciated role of acetylation in protein structure; and a shift in EP300 protein abundance between the cytoplasm and the nucleus. This comprehensive dataset serves as a resource for the investigation of the molecular mechanisms underlying KDACi action in cells and can be interactively explored online in ProteomicsDB.

Effect of quercetin on the protein-substrate interactions in SIRT6: Insight from MD simulations.

SIRT6 is of interest for its promising effect in the treatment of aging-related diseases. Studies have shown quercetin (QUE) and its derivatives have varying degrees of effect on the catalytic effect of SIRT6. In the research, the effect of QUE on the protein-substrate interaction in the SIRT6-mediated mono-ADP ribosylation system was investigated by conventional molecular dynamics (MD) simulations combined with MM/PBSA binding free energy calculations. The results show that QUE can bind stably to SIRT6 with the binding energy of -22.8 kcal/mol and further affect the atomic interaction between SIRT6 and NAD+ (or H3K9), resulting in an increased affinity between SIRT6-NAD+ and decreased SIRT6-H3K9 binding capacity. At the same time, the binding of QUE can also alter some structural characteristics of the protein, with large shifts occurring in the residue regions involving the N-terminal (residues 1-27), Rossmann fold regions (residues 55-92), and ZBD (residues 164-179). Thus, QUE shows great potential as a scaffold for the design of novel potent SIRT6 modulators.

Density functional theory (DFT) studies in HDAC-based chemotherapeutics: Current findings, case studies and future perspectives.

Density Functional Theory (DFT) is a quantum chemical computational method used to predict and analyze the electronic properties of atoms, molecules, and solids based on the density of electrons rather than wavefunctions. It provides insights into the structure, bonding, and behavior of different molecules, including those involved in the development of chemotherapeutic agents, such as histone deacetylase inhibitors (HDACis). HDACs are a wide group of metalloenzymes that facilitate the removal of acetyl groups from acetyl-lysine residues situated in the N-terminal tail of histones. Abnormal HDAC recruitment has been linked to several human diseases, especially cancer. Therefore, it has been recognized as a prospective target for accelerating the development of anticancer therapies. Researchers have studied HDACs and its inhibitors extensively using a combination of experimental methods and diverse in-silico approaches such as machine learning and quantitative structure-activity relationship (QSAR) methods, molecular docking, molecular dynamics, pharmacophore mapping, and more. In this context, DFT studies can make significant contribution by shedding light on the molecular properties, interactions, reaction pathways, transition states, reactivity and mechanisms involved in the development of HDACis. This review attempted to elucidate the scope in which DFT methodologies may be used to enhance our comprehension of the molecular aspects of HDAC inhibitors, aiding in the rational design and optimization of these compounds for therapeutic applications in cancer and other ailments. The insights gained can guide experimental efforts toward developing more potent and selective HDAC inhibitors.

CAMSAP3-mediated regulation of HMGB1 acetylation and subcellular localization in lung cancer cells: Implications for cell death modulation.

BACKGROUND: Deregulation of cell death is a common characteristic of cancer, and resistance to this process often occurs in lung cancer. Understanding the molecular mechanisms underlying an aberrant cell death is important. Recent studies have emphasized the involvement of calmodulin-regulated spectrin-associated protein 3 (CAMSAP3) in lung cancer aggressiveness, its influence on cell death regulation remains largely unexplored. METHODS: CAMSAP3 was knockout in lung cancer cells using CRISPR-Cas9 system. Cell death and autophagy were evaluated using MTT and autophagic detection assays. Protein interactions were performed by proteomic analysis and immunoprecipitation. Protein expressions and their cytoplasmic localization were analyzed through immunoblotting and immunofluorescence techniques. RESULTS: This study reveals a significant correlation between low CAMSAP3 expression and poor overall survival rates in lung cancer patients. Proteomic analysis identified high mobility group box 1 (HMGB1) as a candidate interacting protein involved in the regulation of cell death. Treatment with trichostatin A (TSA), an inhibitor of histone deacetylases (HDACs) resulted in increased HMGB1 acetylation and its translocation to the cytoplasm and secretion, thereby inducing autophagic cell death. However, this process was diminished in CAMSAP3 knockout lung cancer cells. Mechanistically, immunoprecipitation indicated an interaction between CAMSAP3 and HMGB1, particularly with its acetylated form, in which this complex was elevated in the presence of TSA. CONCLUSIONS: CAMSAP3 is prerequisite for TSA-mediated autophagic cell death by interacting with cytoplasmic acetylated HMGB1 and enhancing its release. SIGNIFICANT: This finding provides molecular insights into the role of CAMSAP3 in regulating cell death, highlighting its potential as a therapeutic target for lung cancer treatment.

Neutrophil Elastase Degrades Histone Deacetylases and Sirtuin 1 in Primary Human Monocyte Derived Macrophages.

Neutrophil elastase (NE) is taken up by macrophages, retains intracellular protease activity, and induces a pro-inflammatory phenotype. However, the mechanism of NE-induced pro-inflammatory polarization of macrophages is not well understood. We hypothesized that intracellular NE degrades histone deacetylases (HDAC) and Sirtuins, disrupting the balance of lysine acetylation and deacetylation and resulting in nuclear to cytoplasmic translocation of a major alarmin, High Mobility Group Box 1 (HMGB1), a pro-inflammatory response in macrophages. Human blood monocytes were obtained from healthy donors or from subjects with cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD). Monocytes were differentiated into blood monocyte derived macrophages (BMDMs) in vitro. Human BMDMs were exposed to NE or control vehicle, and the abundance of HDACs and Sirtuins was determined by Western blotting of total cell lysates or nuclear extracts or determined by ELISA. HDAC, Sirtuin, and Histone acetyltransferase (HAT) activities were measured. NE degraded most HDACs and Sirtuin (Sirt)1, resulting in decreased HDAC and sirtuin activities, with minimal change in HAT activity. We then evaluated whether the NE-induced loss of Sirt activity or loss of HDAC activities would alter the cellular localization of HMGB1. NE treatment or treatment with Trichostatin A (TSA), a global HDAC inhibitor, both increased HMGB1 translocation from the nucleus to the cytoplasm, consistent with HMGB1 activation. NE significantly degraded Class I and II HDAC family members and Sirt 1, which shifted BMDMs to a pro-inflammatory phenotype.

Apigenin and its combination with Vorinostat induces apoptotic-mediated cell death in TNBC by modulating the epigenetic and apoptotic regulators and related miRNAs.

Triple-negative breast cancer (TNBC) is a metastatic disease and a formidable treatment challenge as it does not respond to existing therapies. Epigenetic regulators play a crucial role in the progression and metastasis by modulating the expression of anti-apoptotic, pro-apoptotic markers and related miRNAs in TNBC cells. We have investigated the anti-TNBC potential of dietary flavonoid 'Apigenin' and its combination with Vorinostat on MDA-MB-231 cells. At Apigenin generated ROS, inhibited cell migration, arrested the cell cycle at subG0/G1 phases, and induced apoptotic-mediated cell death. Apigenin reduced the expression of the class-I HDACs at the transcriptomic and proteomic levels. In the immunoblotting study, Apigenin has upregulated pro-apoptotic markers and downregulated anti-apoptotic proteins. Apigenin inhibited the enzymatic activity of HDAC/DNMT and increased HAT activity. Apigenin has manifested its effect on miRNA expression by upregulating the tumor-suppressor miR-200b and downregulation oncomiR-21. Combination study reduced the growth of TNBC cells synergistically by modulating the expression of epigenetic and apoptotic regulators. Molecular docking and MD simulations explored the mechanism of catalytic inhibition of HDAC1 and HDAC3 and supported the in-vitro studies. The overall studies demonstrated an anti-TNBC potential of Apigenin and may help to design an effective strategy to treat metastatic phenotype of TNBC.

Attenuation of neuronal ferroptosis in intracerebral hemorrhage by inhibiting HDAC1/2: Microglial heterogenization via the Nrf2/HO1 pathway.

AIM: The class I histone deacetylases (HDACs) implicate in microglial heterogenization and neuroinflammation following Intracerebral hemorrhage (ICH). Ferroptosis has also been reported in the ICH model. However, the relationship between HDAC1/2's role in microglial heterogenization and neuronal ferroptosis remains unclear. METHODS: In both in vivo and in vitro models of ICH, we used Romidepsin (FK228), a selective HDAC1/2 inhibitor, to investigate its effects on microglial heterogenization and neuronal ferroptosis. In the in vitro ICH model using Hemin, a transwell system was utilized to examine how microglia-driven inflammation and ICH-triggered neuronal ferroptosis interact. Immunostaining, Western blotting and RT-qPCR were used to evaluate the microglial heterogenization and neuronal ferroptosis. Microglial heterogenization, neuronal ferroptosis, and neurological dysfunctions were assessed in vivo ICH mice model performed by autologous blood injection. RESULTS: HDAC1/2 inhibition altered microglial heterogenization after ICH, as showing the reducing neuroinflammation and shifting microglia towards an anti-inflammatory phenotype by immunostaining and qPCR results. HDAC1/2 inhibition reduced ferroptosis, characterized by high ROS and low GPx4 expression in HT22 cells, and reduced iron and lipid deposition post-ICH in vivo. Additionally, the Nrf2/HO1 signaling pathway, especially acetyl-Nrf2, activated in the in vivo ICH model due to HDAC1/2 inhibition, plays a role in regulating microglial heterogenization. Furthermore, HDAC1/2 inhibition improved sensorimotor and histological outcomes post-ICH, offering a potential mechanism against ICH. CONCLUSION: Inhibition of HDAC1/2 reduces neuro-ferroptosis by modifying the heterogeneity of microglia via the Nrf2/HO1 pathway, with a particular focus on acetyl-Nrf2. Additionally, this inhibition aids in the faster removal of hematomas and lessens prolonged neurological impairments, indicating novel approach for treating ICH.

Influenza Virus Host Restriction Factors: The ISGs and Non-ISGs.

Influenza virus has been one of the most prevalent and researched viruses globally. Consequently, there is ample information available about influenza virus lifecycle and pathogenesis. However, there is plenty yet to be known about the determinants of influenza virus pathogenesis and disease severity. Influenza virus exploits host factors to promote each step of its lifecycle. In turn, the host deploys antiviral or restriction factors that inhibit or restrict the influenza virus lifecycle at each of those steps. Two broad categories of host restriction factors can exist in virus-infected cells: (1) encoded by the interferon-stimulated genes (ISGs) and (2) encoded by the constitutively expressed genes that are not stimulated by interferons (non-ISGs). There are hundreds of ISGs known, and many, e.g., Mx, IFITMs, and TRIMs, have been characterized to restrict influenza virus infection at different stages of its lifecycle by (1) blocking viral entry or progeny release, (2) sequestering or degrading viral components and interfering with viral synthesis and assembly, or (3) bolstering host innate defenses. Also, many non-ISGs, e.g., cyclophilins, ncRNAs, and HDACs, have been identified and characterized to restrict influenza virus infection at different lifecycle stages by similar mechanisms. This review provides an overview of those ISGs and non-ISGs and how the influenza virus escapes the restriction imposed by them and aims to improve our understanding of the host restriction mechanisms of the influenza virus.

Zinc-Dependent Histone Deacetylases in Lung Endothelial Pathobiology.

A monolayer of endothelial cells (ECs) lines the lumen of blood vessels and, as such, provides a semi-selective barrier between the blood and the interstitial space. Compromise of the lung EC barrier due to inflammatory or toxic events may result in pulmonary edema, which is a cardinal feature of acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS). The EC functions are controlled, at least in part, via epigenetic mechanisms mediated by histone deacetylases (HDACs). Zinc-dependent HDACs represent the largest group of HDACs and are activated by Zn2+. Members of this HDAC group are involved in epigenetic regulation primarily by modifying the structure of chromatin upon removal of acetyl groups from histones. In addition, they can deacetylate many non-histone histone proteins, including those located in extranuclear compartments. Recently, the therapeutic potential of inhibiting zinc-dependent HDACs for EC barrier preservation has gained momentum. However, the role of specific HDAC subtypes in EC barrier regulation remains largely unknown. This review aims to provide an update on the role of zinc-dependent HDACs in endothelial dysfunction and its related diseases. We will broadly focus on biological contributions, signaling pathways and transcriptional roles of HDACs in endothelial pathobiology associated mainly with lung diseases, and we will discuss the potential of their inhibitors for lung injury prevention.

Influenza A Virus and Acetylation: The Picture Is Becoming Clearer.

Influenza A virus (IAV) is one of the most circulated human pathogens, and influenza disease, commonly known as the flu, remains one of the most recurring and prevalent infectious human diseases globally. IAV continues to challenge existing vaccines and antiviral drugs via its ability to evolve constantly. It is critical to identify the molecular determinants of IAV pathogenesis to understand the basis of flu severity in different populations and design improved antiviral strategies. In recent years, acetylation has been identified as one of the determinants of IAV pathogenesis. Acetylation was originally discovered as an epigenetic protein modification of histones. But, it is now known to be one of the ubiquitous protein modifications of both histones and non-histone proteins and a determinant of proteome complexity. Since our first observation in 2007, significant progress has been made in understanding the role of acetylation during IAV infection. Now, it is becoming clearer that acetylation plays a pro-IAV function via at least three mechanisms: (1) by reducing the host's sensing of IAV infection, (2) by dampening the host's innate antiviral response against IAV, and (3) by aiding the stability and function of viral and host proteins during IAV infection. In turn, IAV antagonizes the host deacetylases, which erase acetylation, to facilitate its replication. This review provides an overview of the research progress made on this subject so far and outlines research prospects for the significance of IAV-acetylation interplay.